Migraines are recurrent, often familial, symptom complexes of periodic attacks of vascular headache. Migraines affect approximately 17% of adult women and 6% of adult men (Stewart et al., Neurology, 1994, 44 (suppl. 4), 517-523).
It has been known for some time that sumatriptan, which causes constriction of cranial blood vessels, is an effective treatment for migraine (see, for example, Doenicke et al., Lancet, 1988, Vol. 1, 1309-11; and Feniuk and Humphrey, Drug Development Research, 1992, 26, 235-40). As such, it is the prototypical example of a class of compounds, including rizatriptan, which have recently been classified (Hartig et al.,TIPS, 1996, 17, 103-105) as 5-HT1B/1D receptor agonists.
Activation of 5-HT1B and/or 5-HT1D receptors leads to (1) selective vasoconstriction of certain cranial extracerebral blood vessel segments; (2) pre-junctional inhibition of the release of proinflammatory neuropeptides from sensory nerve terminals in the meninges; and (3) attenuation of central nociceptive neurotransmission by inhibition of neurotransmitter release within the trigeminal nucleus caudalis. It is believed that one or more of these three mechanisms is involved in the anti-migraine action of 5-HT1B/1D receptor agonists such as rizatriptan.
Cyclooxygenase (COX), also known as prostaglandin H synthase, is an enzyme implicated in the mediation of pain, fever and inflammation. It catalyzes the oxidative conversion of arachidonic acid into prostaglandin H2, a key intermediate in the biosynthetic pathway of prostaglandins, prostacyclins and thromboxanes, which in turn mediate a variety of physiological effects both beneficial and pathological.
Recently it was discovered that two COX isoforms exist: COX-1, expressed constitutively in many tissues, and COX-2, an induced isoform having elevated levels of expression in inflamed tissues. COX-1 is thought to be involved in ongoing xe2x80x9chousekeepingxe2x80x9d functions, for example, gastric cytoprotection, while COX-2 is implicated in the pathological effects mentioned above.
Current cyclooxygenase inhibitors such as aspirin, ibuprofen and indomethacin, used as non-steroidal anti-inflammatory drugs (NSAIDs), inhibit both COX-1 and COX-2 and have associated side effects, such as gastrotoxicity, which may be manifested as ulcer formation. COX-2 selective inhibitors act as effective NSAIDs without substantial gastrotoxic side effects. For purposes of this disclosure only, a COX-2 selective inhibitor is defined as a COX inhibitor having a selectivity for the COX-2 isoform relative to the COX-1 isoform.
The treatment of migraines by coadministration of a 5HT agonist and a traditional analgesic, including a NSAID has been described in international patent application WO98/06392.
It has now been found that migraines can be more effectively treated and/or controlled by the co-administration of a 5-HT1B/1D receptor agonist in combination with a COX-2 selective inhibitor, than with a 5HT1B/1D agonist alone, and more safely than with a traditional analgesic in combination with a 5HT agonist.
The present invention relates to a method of treating or preventing migraines in a mammalian patient in need thereof, which comprises administering to said patient an anti-migraine effective amount of a combination of a COX-2 selective inhibitor and a 5-HT1B/1D receptor agonist.
The invention also relates to a pharmaceutical composition comprising a COX-2 selective inhibitor, a 5-HT1B/1D receptor agonist and a pharmaceutically acceptable carrier therefore.